MicroRNA-mediated PTEN downregulation as a novel non-genetic mechanism of acquired resistance to PI3Kα inhibitors of head & neck squamous cell carcinoma

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates Pub Date : 2025-05-11 DOI:10.1016/j.drup.2025.101251

Claudio Pulito , Sebastiano Vaccarella , Alina Catalina Palcau , Federica Ganci , Renata Brandi , Carlotta Frascolla , Andrea Sacconi , Valeria Canu , Anna Benedetti , Valentina De Pascale , Sara Donzelli , Anne-Sophie Fisch , Valentina Manciocco , Renato Covello , Fulvia Pimpinelli , Aldo Morrone , Francesco Fazi , Raul Pellini , Paola Muti , Jalna Meens , Giovanni Blandino

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引用次数: 0

Abstract

Aims

Head and neck squamous cell carcinomas (HNSCCs) frequently harbor alterations in the PI3K signalling axis and, particularly, in the PIK3CA gene. The promising rationale of using PI3K inhibitors for the treatment of HNSCC has, however, clashed with the spontaneous development of resistance over time.

Methods

To identify valuable targets for overcoming acquired resistance to PI3Kα inhibitors in HNSCC, we performed microRNA profiling on a cohort of HNSCC PDXs that were treated with alpelisib, including both responsive and resistant tumors. Using CRISPR/Cas9, siRNA, and PTEN-/- isogenic and alpelisib-resistant cell models, we examined the role of PTEN in resistance acquisition. Phospho-proteomic analysis identified PTEN-dependent phosphorylation events, while PI3Kα inhibitor-resistant organoids were used to assess PLK1 inhibitor efficacy.

Results

We identified microRNAs altered in resistant PDXs, including members of the miR-17–92 cluster. Mechanistically, we observed that the hyperactive c-Myc was recruited to MIR17HG regulatory regions in alpelisib-resistant cells, sustaining miR-17–5p, miR-19b-3p, and miR-20a-5p expression, which downregulated PTEN. PTEN knockout or depletion conferred alpelisib resistance in HNSCC cells. We identified PTEN-dependent phosphorylation events, such as p-PLK1-T210, involved in resistance. Interestingly, pharmacological inhibition of PLK1 strongly reduced the viability of PI3Kα-resistant organoids derived from HNSCC PDXs and cell line models.

Conclusion

Overall, this study unveils a novel, microRNA-driven, non-genetic mechanism contributing to acquired resistance to PI3Kα inhibitors in HNSCC. Indeed, linking hyperactive c-Myc to sustain miR-17–92 expression and consequent PTEN downregulation, we also propose that targeting PTEN-dependent downstream effectors, such as PLK1, may offer a powerful therapeutic strategy for resistant HNSCC.

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microrna介导的PTEN下调作为头颈部鳞状细胞癌对PI3Kα抑制剂获得性耐药的一种新的非遗传机制

头颈部鳞状细胞癌（HNSCCs）经常发生PI3K信号轴的改变，特别是PIK3CA基因的改变。然而，使用PI3K抑制剂治疗HNSCC的有希望的原理与随着时间的推移自发产生的耐药性发生了冲突。为了确定HNSCC中克服对PI3Kα抑制剂获得性耐药的有价值靶点，我们对一组接受alpelisib治疗的HNSCC pdx进行了microRNA分析，包括反应性和耐药性肿瘤。利用CRISPR/Cas9、siRNA和PTEN-/-等基因和alpelisib耐药细胞模型，我们研究了PTEN在耐药获得中的作用。磷酸化蛋白质组学分析确定了pten依赖性磷酸化事件，而PI3Kα抑制剂抗性类器官用于评估PLK1抑制剂的有效性。我们鉴定了耐药pdx中发生改变的microrna，包括miR-17-92簇的成员。在机制上，我们观察到，在抗alpelisib细胞中，过度活跃的c-Myc被募集到MIR17HG调控区域，维持miR-17-5p、miR-19b-3p和miR-20a-5p的表达，从而下调PTEN。PTEN基因敲除或耗尽可使HNSCC细胞对alpelisib产生抗性。我们确定了pten依赖性磷酸化事件，如p-PLK1-T210，参与耐药性。有趣的是，PLK1的药理抑制强烈降低了来自HNSCC PDXs和细胞系模型的pi3k α抗性类器官的活力。总之，本研究揭示了HNSCC对PI3Kα抑制剂获得性耐药的一种新的、微rna驱动的非遗传机制。事实上，将过度活跃的c-Myc与维持miR-17-92表达和随后的PTEN下调联系起来，我们还提出靶向PTEN依赖的下游效应物，如PLK1，可能为耐药HNSCC提供强大的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Resistance Updates 医学-药学

CiteScore

26.20

自引率

11.90%

发文量

审稿时长

29 days

期刊介绍： Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research